Drug Interactions between doravirine / lamivudine / tenofovir disoproxil and sotorasib

GENERALLY AVOID: Coadministration with moderate inducers of CYP450 3A4 may significantly decrease the plasma concentrations of doravirine, which is primarily metabolized by the isoenzyme. In 10 study subjects, administration of a single 100 mg dose of doravirine with the potent CYP450 3A4 inducer rifampin (600 mg once daily) decreased doravirine peak plasma concentration (Cmax), systemic exposure (AUC) and trough plasma concentration (C24hr) by an average of 57%, 88% and 97%, respectively, compared to administration of doravirine alone. When doravirine was administered with the moderate CYP450 3A4 inducer rifabutin (300 mg once daily) in 12 study subjects, doravirine Cmax did not change, but AUC and C24hr decreased by an average of 50% and 68%, respectively. In addition, when doravirine 100 mg once daily was initiated following cessation of treatment with efavirenz (600 mg once daily) in 17 study subjects, doravirine Cmax, AUC, and C24hr decreased by an average of 35%, 62% and 85%, respectively, on the first day and 14%, 32% and 50%, respectively, 14 days later. Although coadministration of doravirine with other moderate CYP450 3A4 inducers has not been evaluated, reduced efficacy of doravirine may occur. The extent to which other, less potent CYP450 3A4 inducers may affect doravirine is unknown.

MANAGEMENT: Given the risk of reduced viral susceptibility and resistance development associated with subtherapeutic antiretroviral drug levels, concomitant use of doravirine with moderate CYP450 3A4 inducers should generally be avoided. If coadministration is necessary, some authorities recommend that the doravirine dose be increased to 100 mg twice daily (approximately 12 hours apart) (UK).

MONITOR: Coadministration with sotorasib may increase the plasma concentrations of drugs that are substrates of the P-glycoprotein (P-gp) and/or breast cancer resistance protein (BCRP) membrane transporters. The proposed mechanism involves enhanced absorption and bioavailability of substrate drugs due to inhibition of intestinal P-gp- and BCRP-mediated efflux by sotorasib. Inhibition of P-gp and BCRP transport in other organs such as the liver and kidney may also contribute in some cases, especially for non-oral drugs. When digoxin, a sensitive P-gp substrate, was coadministered with sotorasib, digoxin peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 91% and 21%, respectively. When rosuvastatin, a BCRP substrate, was coadministered with sotorasib, rosuvastatin Cmax and AUC increased by 70% and 34%, respectively.

MANAGEMENT: Caution is advised when sotorasib is used concurrently with drugs that are P-gp and/or BCRP substrates, particularly those with a narrow therapeutic range. The prescribing information recommends avoiding coadministration of sotorasib with P-gp and BCRP substrates for which minimal concentration changes may lead to serious toxicities. If coadministration is required, dosage adjustments as well as clinical and laboratory monitoring may be appropriate whenever sotorasib is added to or withdrawn from therapy. The prescribing information for concomitant medications should be consulted to assess the benefits versus risks of coadministration of a P-gp and BCRP inhibitor like sotorasib and for any dosage adjustments that may be required.